Chronic renal failure (CRF) is a common disease of childhood and often leads to severe renal osteodystrophy (ROD) which is crippling and difficult to surgically correct. Advances in our understanding of the biochemistry and metabolism of vitamin D point to its central role in regulating calcium and phosphorus homeostasis and bone morphology in health and disease, especially CRF. On one hand, experimental evidence supports the need for some form of vitamin D to treat the ROD in CRF. On the other hand, despite evidence suggesting that 1,25 (OH)2D3 is the most potent and biologically active vitamin D metabolite, there are no controlled studies comparing it with the other major vitamin D metabolite, 25(OH)D3 and/or conventional vitamin D3 or dihydrotachysterol (DHT, the present treatment of choice for ROD). We conducted a pilot study of childhood ROD to: (1) learn how early ROD begins in childhood CRF; (3) compare clinical, biochemical and radiographic ("older") diagnostic techniques with hormonal (PTH) and quantitative bone histology ("newer") diagnostic techniques and; (3) assess the long-term therapeutic efficacy of oral 25(OH)D3. Results showed: (1) subclinical ROD begins early in CRF (GFR approximately 25-50 mls/min.1/1.73M2); (2) initial bone biopsies revealed predominantly osteomalacia or combinations of osteomalacia and hyperparathyroidism and (3) after 2 years, 25(OH)D3 cured osteomalacia in most children and improved hyperparathyroidism. Linear growth increased, serum alkaline phosphatase and PTH fell, and there was no hypercalcemia. These results warrant a controlled therapeutic trial of vitamin D in childhood ROD, comparing the long term effects of DHT, 1,25(OH)2D3 and 25 (OH)D3. Therapeutic response will be evaluated by serial measurements of growth velocity, serum Ca, Pi, alkaline phosphatase, vitamin D metabolites, PTH and quantitative bone histology.